表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌相关不良反应研究进展

表皮生长因子受体酪氨酸激酶抑制剂（EGFR—TKI）治疗非小细胞肺癌（NSCLC）有较好疗效,目前临床常用药物为吉非替尼,厄洛替尼和埃克替尼。随着EGFR—TKI在临床的广泛应用,关于其不良反应的研究也不断深入。EGFR—TKI主要不良反应为皮疹、甲沟炎、毛发改变、腹泻、肝脏损害和间质性肺疾病等。引起不良反应的机制大多不明确。对于较常见的皮疹、甲沟炎等不良反应,较轻时可给予对症处理,严重时应减量或停药;对于较严重的肝脏损害或间质性肺疾病,给予对症治疗的同时要定期检测肝、肺功能。     

Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo

Summary  Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with non-small cell lung cancer (NSCLC). However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the antitumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor (Zhao260054). In vitro studies in a panel of four different human lung cancer cell lines revealed that Zhao260054 inhibited cell proliferation with high potency and induced G₀/G₁ arrest of cell cycle and apoptosis. Zhao260054 markedly reduced phosphorylation of EGFR and inhibited activation of ERK1/2 and AKT. Oral administration of Zhao260054 (200 mg/kg/day) to BALB/c nude mice bearing SPC-A1 xenografts significantly retarded tumor growth. In conclusion, Zhao260054 has potent antitumor activity on human lung cancer in vitro and in vivo.     

Severe lung and skin toxicity during treatment with gemcitabine and erlotinib for metastatic pancreatic cancer

Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor erlotinib is a new treatment option for patients with advanced pancreatic cancer. The nonhematological side effects of this regimen mainly include diarrhea and skin rash. For each of these drugs, gemcitabine and erlotinib, lung toxicities have been described previously. In this report, we present the first case of a nonlung cancer patient experiencing not only acne-like skin toxicity, but subsequently also severe interstitial lung disease during therapy with gemcitabine and erlotinib. Both therapeutic agents were suspected as a possible cause of this adverse event. An interaction between gemcitabine and erlotinib might have also contributed to the pathogenesis of this pulmonary toxicity. Treatment with high-dose steroids was, however, very effective in our patient and a complete recovery appeared within a few days. Thus, pulmonary side effects should be regarded carefully in pancreatic cancer patients receiving palliative therapy with gemcitabine and erlotinib.     

Maintenance therapy for advanced non-small-cell lung cancer: switch versus continuation

INTRODUCTION: The concept of maintenance therapy in lung cancer has stirred a great deal of interest over the last decade. Several randomized studies have been conducted to find out the usefulness of maintenance therapies for advanced non-small-cell lung cancer (NSCLC). AREAS COVERED: This article reviews the major benchmark clinical trials and strategies in the field of maintenance chemotherapy in advanced NSCLC. The two strategies used in maintenance therapy are: i) continuation maintenance - continuation of one of the initial treatments; and ii) switch maintenance - switching to a different agent not administered as initial treatment. Both chemotherapeutic and molecular targeted agents have been studied in the maintenance setting. These include docetaxel, gemcitabine, pemetrexed, bevacizumab, erlotinib and gefitinib. This paper discusses the relevant clinical trials using these agents and the two different strategies in the maintenance therapy in advanced NSCLC. EXPERT OPINION: Despite some controversy regarding the choice or the timing of the maintenance therapy, most of the clinical trials have demonstrated a significant improvement of progression-free survival, translating to a survival benefit with pemetrexed and erlotinib. The approval of pemetrexed and erlotinib by the FDA has certainly shifted the pendulum towards maintenance therapy.     

Successful treatment with erlotinib after gefitinib-induced interstitial lung disease: a case report and literature review

Gefitinib and erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), are widely used anticancer drugs for patients with non-small cell lung cancer (NSCLC), especially for those with EGFR-activating mutations. Both agents are considered to be less toxic compared with cytotoxic drugs; however, serious adverse events including interstitial lung disease (ILD) which can be fatal occur rarely. After such an event, physicians avoid to use another TKI. In such cases, patients and physicians are forced to make difficult decisions or reluctantly choose TKI when there is no other option. Here we report a case of a patient with lung adenocarcinoma who showed good recovery from gefitinib-induced ILD by high-dose corticosteroid therapy. The patient was then administrated erlotinib as second-line chemotherapy and showed tumor shrinkage without ILD after 6 months of treatment. We discuss the common features of the cases in the previous documentations and ours which were successfully retreated with erlotinib after gefitinib-induced ILD had previously developed.     

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

The epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib resistance and able to maintain S6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.     

Erlotinib and gefitinib for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a preclinical comparison

Erlotinib and gefitinib, two inhibitors of the epidermal growth factor receptor (EGFR), can stimulate apoptosis and differentiation of myeloid cell lines that lack EGFR, unveiling a novel, therapeutically exploitable off-target effect of tyrosine kinase inhibitors. Here, we performed a side-by-side comparison of erlotinib and gefitinib effects on a broad spectrum of malignant myeloid cell lines, as well as on primary myeloblasts freshly purified from the bone marrow of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Both erlotinib and gefitinib induce apoptosis of a cell line (KG-1) that represents AML, and differentiation in another cell line (P39) derived from a patient with high-risk MDS. In this setting, erlotinib was more efficient than gefitinib. Erlotinib and gefitinib were equipotent in inducing apoptosis of primary CD34⁺ myeloblasts from MDS and AML patients, yet had no toxic effect on CD34⁺ progenitor cells from healthy donors. Although the response of individual MDS and AML patients in vitro was highly heterogeneous, the pro-apoptotic effects of erlotinib and gefitinib correlated significantly. These results suggest that erlotinib and gefitinib share a mechanistically related off-target effect that may be taken advantage of for the therapy of MDS and AML.     

Gefitinib for non-small-cell lung cancer treatment

INTRODUCTION: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. AREAS COVERED: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC. EXPERT OPINION: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Erlotinib: new drug. Non small-cell lung cancer: like gefitinib, no established advantage

(1) There is no standard third-line treatment for locally advanced or metastatic non small-cell lung cancer. (2) Erlotinib, like gefitinib, inhibits the tyrosine kinase activity of the epidermal growth factor (EGF) receptor, and has been licensed for sale in the European Union. (3) A double-blind placebo-controlled trial involving 713 patients who had failed to respond to one or two previous chemotherapy regimens showed that erlotinib increased the median survival time by about 2 months (6.7 versus 4.7 months), without improving the quality of this survival. It is not possible to predict precisely which patients are most likely to respond to erlotinib. (4) In first-line treatment, erlotinib was no more effective than placebo as an adjunct to chemotherapy in 2 trials involving 1079 and 1172 patients. (5) The adverse effect profile of erlotinib seems similar to that of gefitinib, mainly consisting of gastrointestinal disturbances (especially diarrhoea: 54% of patients versus 18% on placebo), skin rash (75% versus 17%), and ocular disorders (conjunctivitis: 12% versus 2%). In the comparative trial of second- or third-line treatment, 0.8% of patients developed interstitial pneumonia. (6) Erlotinib, like gefitinib, is metabolized by the cytochrome P450 isoenzyme CYP3A4, potentially creating a high risk of interactions. (7) In practice, the limited benefit of erlotinib seems to be outweighed by its frequent adverse effects. Erlotinib should therefore only be used in clinical trials designed to identify subgroups of patients in whom the risk-benefit balance may be favourable.     

Epidermal growth factor receptor inhibitors: an update on their development as cancer therapeutics

Therapeutic agents targeting the epidermal growth factor receptor (EGFR) have recently been approved for use in patients based on the results of large-scale phase II studies involving patients with advanced refractory non-small-cell lung cancer (NSCLC). Disappointingly, results from phase III trials of gefitinib in combination with standard chemotherapy regimens for the treatment of NSCLC were negative. While results from phase III trials with other agents such as erlotinib and cetuximab will be reported in the next 12 to 18 months, the early results raise a number of questions regarding the development of these agents, including patient selection (e.g., disease, stage, prior therapy, EGFR or other biomarker expression) and combinations with standard treatment regimens as well as hormonal agents, radiation or other novel agents which will require further elucidation. Early data suggest a number of potential roles for these agents in the modulation of resistance and in combination with other inhibitors of signal transduction.     

Safety of gefitinib in non-small cell lung cancer treatment

ABSTRACT

Introduction: The development of EGFR TKI and the subsequent identification of activating EGFR mutations have dramatically changed how NSCLC is treated. With its recent approval by the US Food and Drug Administration, gefitinib adds to the list of recommended first-line treatments for lung cancer harboring EGFR mutations, which hitherto includes erlotinib and afatinib.

Areas covered: This review summarizes the pharmacological property, clinical efficacy, and safety of gefitinib in major clinical trials and post-marketing studies.

Expert opinion: Gefitinib is a well-tolerated treatment for advanced NSCLC. The most common adverse events are skin reaction and diarrhea, both of which are generally mild, noncumulative, and manageable. Other side effects such as interstitial lung disease and liver toxicity are less common but can be serious. Which EGFR TKI is the preferred first-line treatment is a matter of debate. Gefitinib and erlotinib have comparable efficacy, whereas afatinib may exert superior clinical activity over gefitinib. In terms of the most common toxicities of skin reaction and diarrhea, gefitinib may be the most tolerable of the three. Hence, despite being the earliest EGFR TKI developed, gefitinib continues to be one of the first-line treatments for advanced EGFR-mutated NSCLC, especially when skin and gastrointestinal toxicity is a concern.     

晚期非小细胞肺癌维持治疗的研究进展

维持治疗分为继续维持治疗和换药维持治疗。研究证实,培关曲塞是一种既可用于换药维持治疗、也可用于继续维持治疗的晚期非小细胞肺癌化疗药物。另外,酪氨酸激酶抑制剂亦是一类非常有效的维持治疗选择,其中吉非替尼和厄洛替尼已被有关指南推荐用作维持治疗药物,但目前只能用于换药维持治疗。     

Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, caused by the presence of different clinically relevant molecular subtypes. Genetic mutations are emerging as potential biomarkers of response and treatment selection in patients with NSCLC. Over the past few years, activating mutations of epidermal growth factor receptor (EGFR) have been recognized as the most important predictor of response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib and also as a favourable prognostic factor. The RAS genes, including H-RAS, K-RAS and N-RAS, encode a family of proteins regulating cell growth, differentiation and apoptosis. Mutations in the K-RAS gene, mainly in codons 12 and 13, have been found in 20-30% of NSCLC tumor samples and occur most commonly, but not exclusively, in adenocarcinoma histology and in heavy smokers. In NSCLC, the presence of K-RAS mutations has generally been considered to be associated with worse prognosis and resistance to systemic therapy in the adjuvant as well as the metastatic setting. In early stage NSCLC, the prognostic role of K-RAS mutations has been evaluated in several studies without definitive conclusion. On the other hand, in advanced NSCLC, the presence of K-RAS mutations identifies a subgroup of patients who do not respond to EGFR-TKI therapy but, at the same time, a positive survival effect from EGFR-TKIs cannot be excluded in these patients. Similarly, K-RAS mutational status does not predict benefit from the anti-EGFR monoclonal antibody cetuximab, highlighting the biological difference between lung cancer and colorectal cancer. As a result of the lack of conclusive data, K-RAS mutations do not represent a validated biomarker for the negative selection of patients who are candidates for anti-EGFR therapy. The aim of this article is to review and discuss the data on the prognostic and predictive value of K-RAS mutations in NSCLC.     

Epidermal growth factor receptor inhibitors in non-small cell lung cancer

Aberrant epidermal growth factor receptor (EGFR) signalling contributes to neoplastic transformation and EGFR inhibition by antibodies and small molecules inhibits cancer cell proliferation and survival. In previously treated patients with non-small cell lung cancer, the administration of gefitinib and erlotinib are associated with objective tumour response rates of 8-19%. However, only erlotinib has been shown definitively to improve patient survival. The likelihood of benefit may be determined by the presence of specific genotypic abnormalities in EGFR or downstream pathway components. Additional evaluation to determine optimal dose/schedule of the agents combined with standard treatments and with other targeted agents in appropriately selected patients are areas of active research.     

厄洛替尼致间质性肺疾病的特点、机制及防治简

厄洛替尼为表皮生长因子受体酪氨酸激酶抑制剂（EGFR—TKI）,临床用于治疗非小细胞肺癌。问质性肺疾病（ILD）是厄洛替尼严重而少见的不良反应,发生率为0．1％～4．8％,病死率为0．8％～2．4％。厄洛替尼引起ILD的中位时间为用药22d,临床表现为干咳、低热、呼吸困难等,影像学检查可见双肺弥漫性磨玻璃样阴影,实验室检查显示低氧血症。男性、高龄、有基础肺部病变及吸烟等为危险因素。厄洛替尼致ILD的主要机制为免疫介导和药物的直接毒性。避免对高危患者用药、使用低剂量、避免与其他化疗药物和／或放射治疗同步应用、加强呼吸功能监测是预防厄洛替尼致ILD的有效措施。一旦发生ILD应立即停用厄洛替尼,换用其他EGFR—TKI。厄洛替尼致ILD的治疗以抑制炎症反应及防止肺纤维化为主要目的,主要措施包括吸氧、应用糖皮质激素,预防感染和对症治疗。     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in approximately 10-20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in ~ 10 – 20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Interstitial lung disease in lung cancer: separating disease progression from treatment effects.

Lung cancer often develops in individuals with pre-existing pulmonary and cardiac pathology. Many of these individuals with pre-existing pathology are also at risk of occupational lung disease. New and worsening symptoms can be secondary to pre-existing pathology, progressive cancer or treatment. Pulmonary toxicity, including interstitial lung disease, following radiotherapy and conventional cytotoxic chemotherapy (e.g. cyclophosphamide, bleomycin), has been recognised for many years. Pulmonary toxicity also occurs with the newer classes of cytotoxic agents, including the deoxycytidine analogue gemcitabine. A small percentage (0.88%) of patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib have developed interstitial lung disease. This complication has been reported at a higher frequency in Japanese patients than in US patients (1.9% vs 0.34%, respectively) and in those with pre-existing pulmonary fibrosis. This review discusses the difficulties in both recognition and treatment of gefitinib-associated interstitial lung disease. Symptoms are vague, such as dyspnoea, cough and fever and can be difficult to differentiate from progressive disease, co-existing morbidity and new pulmonary pathology. Diagnosis is, therefore, by rigorous investigation to exclude all other differential diagnoses. Treatment, at present, is supportive and includes discontinuation of gefitinib, oxygen supplementation, high-dose corticosteroids and antibacterials.     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.